The invention generally relates to the treatment of cancer, and, more specifically, to the treatment of tumors, including, but not limited to human sarcomas, melanomas, and carcinomas, including their metastases. Specifically it relates to a method for inducing cancer remission through immune stimulation caused by administration of a preparation produced by human monocytes.
Therapy for cancer has largely involved the use of radiation, surgery and chemotherapeutic agents. However, results with these treatment modalities, while beneficial in some tumors, has only marginal or no effect in most. Furthermore, these approaches often have unacceptable toxicities. It is generally recognized that a single clonogenic malignant cell can give rise to sufficient progeny to kill the host, and therefore, to successfully treat cancer the entire population of neoplastic cells must be eradicated. This concept implies that if one is to achieve a cure, total excision of a tumor is necessary for a surgical treatment, and complete destruction of all cancer cells is needed for radiation treatment. In practice this is rarely possible and when there are metastases, it is impossible.
The term xe2x80x9cchemotherapyxe2x80x9d can be defined as the treatment of disease with chemical substances. Used herein chemotherapy refers to application of anti-neoplastic chemicals to an individual with cancer. The goal of chemotherapy is selective toxicity to cancer cells. However, selectivity has been the major problem with chemotherapy agents. The majority of anticancer drugs are indiscriminate at anti-neoplastic concentrations. Typically chemotherapy agents have negative hematological effects (e.g., cessation of mitosis and disintegration of formed elements in marrow and lymphoid tissues), immunosuppressive activity (e.g., depressed white blood cell counts), and negative impacts on epithelial tissues and reproductive tissues, and the nervous system. Chemotherapy can also increase the incidence of secondary cancers.
Immune-stimulating cytokines have been used in, the treatment of cancer. Recombinant interleukin 2 and gamma interferon are now commonly used as adjuvant therapy for renal cell carcinoma. As early as the early 1900""s immune therapy for cancer has shown promise. William Coley used a mixed bacterial vaccine in the treatment of sarcomas with mixed success. It is now thought that this mixed bacterial vaccine induced in vivo production of cytokines which were responsible for tumor regression.
In addition to cytokine therapy, other immune-enhancing therapies are currently under investigation. These include dendritic cell therapy, autologous tumor vaccines, genetically altered vaccines, and lymphocytes therapies.
The above immune therapies all have limitations. Recombinant cytokines are effective in a minority of cases. Dendritic cell therapy is time-consuming and expensive and is rarely effective. Autologous tumor vaccines have variable immunogenicity and therefore variable efficacy, and genetically altered vaccines are expensive and are also variably effective.
It is now being recognized that a primary localized immune defect of cancerous tissue is that of reduced ability to adequately present antigen to cytotoxic T cells. Dendritic cells are also known as professional antigen presenting cells and are chiefly responsible for the contextual presentation of antigen to CTLs. It has recently been found that several types of tumor tissue contain dendritic cells in adequate number to perform antigen presentation, however, the intra- and peri-tumoral dendritic cells are immature, and therefore lack the necessary co-stimulatory molecules to effectively present antigen to CTLs. It has also recently been discovered that immature dendritic cells can be forced to mature and become more effective antigen presenting cells by contacting the immature cells with certain cytokines. The most effective preparation of cytokines for inducing dendritic cell maturation is a mixture of cytokines and other unknown molecules found in the growth medium of cultured monocytes exposed to gamma globulin. Herein referred to as monocyte conditioned medium (MCM). Many investigators are currentl using MCM as a maturing agent in human trials of dendritic cell therapy.
Therefore, the need exists for a method of effecting remissions from neoplastic diseases. In particular a method that effects remissions from cancer without causing serious, long-term side effects.
Of interest was a treatment for cancer which had rapid anti-tumor activity in doses that did not induce intolerable or lasting side effects. A number of substances have been used in the past to activate monocytes or macro,phages and as immune activators. When such substances are administered directly to a patient, they can produce severe side effects. When such substances are administered to macrophages in tissue culture, they induce those cells to produce a number of immune stimulatory molecules including cytokines. The inventors wondered if a preparation composed of the conditioned medium for these cells would be usable as a cancer treatment if administered directly to a patient. It was surprisingly found that monocyte conditioned medium (MCM) when administered to a cancer patient did have anti-neoplastic activity. In addition, A MCM was effective as an antitumor treatment in doses that did not induce intolerable or lasting side effects.
Therefore, the present invention provides a unique solution to the problems with many cancer therapies by providing a therapeutic method for the treatment of cancer by inducing remissions in humans having cancer without serious, long-term side effects. The method in this invention can result in short-term side effects that are clinically manageable. However, the methods do not result in any long-term side effects, in particular immune suppression. The method of this invention will be effective for a broad spectrum of cancerous diseases.
Disclosed is a method for the treatment of cancer in a patient which includes, collecting monocytes from the peripheral blood of the patient or a donor, culturing the monocytes in a culture medium which also contains a macrophage stimulator, collecting the culture medium, and administering the culture medium to a patient. The culture medium can be administered topically, preferably with a transdermal carrier, parenterally, intravenously, peritumorally, and/or intratumorally. The method may also involve concentrating the culture medium, preferably by lyophilization, column chromatography, or filtration. The cancer treatable by this method includes carcinomas, sarcomas, and leukemias and lymphomas and their metastases. In one embodiment, the cancer is squamous cell cancer of the skin, prostate cancer, uterine sarcoma, osteosarcoma, and squamous cell head or neck cancer.
The macrophage stimulator can be a cytokines, bacterial component, or fungal component. Preferably, the macrophage stimulator is gamma-globulin, fungi, fungal cytoplasmic components, fungal cell wall components, bacteria, bacterial cytoplasmic components, bacterial cell wall components, mycoplasma, mycoplasma cytoplasmic components, mycoplasma cell wall components, endotoxins (LPS), muramyl peptides, glucans, Colony Stimulating Factors (CSFs)xe2x80x94GM-CSF or G-CSF, melatonin, lipoproteins, phytohaemagglutinin (PHA), adenosine triphosphate (ATP), ATP metabolites or ATP analogues.
A further aspect of the invention is a pharmaceutical preparation for the treatment of cancer comprising a monocyte-conditioned medium obtained by the method disclosed above.